Process for the manufacture of multiple unsaturated aliphatic compounds



United States Patent 3,401,210 PROCESS FOR THE MANUFACTURE OF MULTIPLEUNSATURATED ALlPI-IATIC COMPOUNDS Hendrik Paul de Jongh and FilippnsJohannes Zeelen, Oss, Netherlands, assignors to Organon Inc., WestOrange, N.J., a corporation of New Jersey N0 Drawing. Filed Oct. 3,1966, Ser. No. 583,983 Claims priority, application Netherlands Oct. 18,1965, 6513473 4 Claims. (Cl. 260-678) ABSTRACT OF THE DISCLOSUREMultiple unsaturated compounds of the formula HC COH=CR in which R is analkyl group of 1 to 6 carbon atoms, are prepared by etherifying thehydroxyl group of a compound of the formula a HC=CCH2CR in which R is analkyl group of 1 to 6 carbon atoms, and treating the ether with an alkylamide in liquid ammonia or a lower aliphatic amine. The products areintermediates for the synthesis of compounds of the vitamin A series.

The invention concerns a process for the manufacture of a multipleunsaturated aliphatic compound of the formula:

CH3 HCECCH=(|3-R in which R represents an alkyl group with one to sixcarbon atoms, by conversion of a tertiary hydroxyl group of the startingmaterial into an ether grouping, followed by splitting olf said groupingwhile forming a double bond.

It has been known to convert alcohols of the type HCECCH2CHR in which Rrepresents, for example, a lower alkyl group into an enyn by firstpreparing their tosylate, followed by their treatment with alkali, toobtain a double bond while splitting off of p-toluene sulphonic acid. Onpage 108 of Raphaels Handbook, Acetylenic Compounds in OrganicSynthesis, published in London by Butterworths Scientific Publications,1959, this method is described. It is not well usable, however, if thestarting product contains a tertiary hydroxyl group, because thetosylate of it is hard to obtain in a good yield.

Further it has been known from Berichte, 82, 276 (1949), first toconvert the alcohol 1-ethoxy-3-hydroxy- 3-methyl-hex-5-yne into thecorresponding bromide, and to split off from it the hydrobromic acidwith potassium hydroxide solution. It requires, however, reactiontemperatures of 180-l85 C., whereas yields are slight.

A process has been found now for the manufacture of multipleunsaturated, aliphatic compounds, by conversion of a hydroxyl group ofthem into a grouping that can be split off, while forming a double bond,followed by the introduction of the double bond, characterized in that acompound of the general formula 3,401,210 Patented Sept. 10, 1968 inwhich R represents an alkyl group whether or not branched with one tosix carbon atoms, possibly substituted, is converted into an ether,treating it subsequently with an alkali metal amide in liquid ammonia,or a lower aliphatic amine. It is surprising that the ethers used asintermediate products can be converted in the alkali medium according tothe invention, as it has been known that ,B-acetylene ethers are stablein alkaline medium, as goes forward, for instance, from the synthesis ofl-methoxy-but-3-yne from acetylene sodium and l-methoxy-Z- bromoethanein liquid ammonia, as described in J. Am. Chem. Soc., 59, 213 (1937).With the present method yields can be obtained of, for instance, 70%.

Further it has been found that, starting from the above compounds, inwhich R represents the group in which R represents an alkyl group with1-6 carbon atoms, hence from 1,1-dialkoxy-3-hydroxy-3-methyl-hex- S-yne,after etherifying of the hydroxyl group, 2 other groups can be split offwhile forming 2 double bonds to obtain thel-alkoxy-3-methyl-hexa-1,3-dien-5-yne. The said starting products areknown compounds, described in the U.S. patent specification 2,676,994and used as intermediates for the synthesis of vitamin A.

The present final products are important intermediates for the synthesisof compounds of the vitamin A series. Thus by the coupling of1-alkoXy-3-methyl-hexa-1,3-dien- S-yne with fl-ionone compounds can beobtained directly of the carbon skeleton of vitamin A, as described inthe published Netherlands patent application 6,404,175. These finalproducts are also of importance for the synthesis of carotenes andcarotenoids.

The ethers, functioning as intermediates in the method of preparationaccording to the invention, may be prepared in a conventional manner.Preferably they are prepared by the addition of the alcohol to avinylether of the general formula:

in which R R and R represent hydrogen or an alkyl group with 1-6 carbonatoms and R; an alkyl group with 1-6 carbon atoms. Of these vinylethersespecially those are applied of the formula: R O-CH=CH in which Rrepresents an alkyl group with 1-4 carbon atoms, which ethers can bebought at a low price and give high yields. The splitting off of theether group, while forming a double bond, is performed with an alkalimetal amide, such as lithium, sodium and potassium amide, in liquidammonia or a lower amine, such as methyl, ethyl and triethyl amine,which solvents may be diluted, if desired, with, for instance, benzene,toluene, dimethylformamide, dimethylacetamide and tetrahydrofuran. Theamide may be added either to the ammonia or may be formed in it bydissolving the required amount of alkali metal in the presence of asmall amount of ferrinitrate as catalyst.

The temperature at which the splitting off of the ether group occursdepends on the strength of the base used. When potassium amide is used,this reaction proceeds satisfactorily at a temperature of 30 C. to -65C.

Further it has been found that the largest yields are obtained with theuse of 5-15 mols of alkali metal amide per mol of ether. The metalcompound formed in this reaction is decomposed with, for instance,ammonium chloride or a dilute mineral acid. The final product may beisolated from the reaction mixture by extraction with a solvent, forinstance, ether. After drying the extract and removing the solvent thefinal product may be purified by fractionated distillation at reducedpressure.

According to the NMR-spectrum a mixture of chiefly two stereo-isomers isformed in the preparation of hexadienyne, viz the cis-trans and thetrans-trans isomer of the respective formulae:

The refraction indices observed of the mixture of isomers ofl-methoxy-hexadienyne are between 1.52 and 1.56, dependent on the ratioof cis-trans. By means of gaschromatography they may be separated, ifdesired. Both isomers can be used in the synthesis of vitamin A.

As examples of starting products of the present process are mentionedthe compounds of the Formula I, in which R represents a methyl, ethyl,propyl, isopropyl and butyl group, which may be substituted by ahydroxyl group, an acyloxy group, an alkoxy group or by an amino group.

The ethers used as intermediates may be derived from, for instance, analiphatic alcohol, such as methanol, ethanol, propanol and t-butanolfrom aromatic hydroxyl compounds, such as phenol, p-nitrophenol,p-chlorophenol and p-methoxyphenol, as well as from heterocycliccompounds, such as dihydropyran.

As examples of suitable vinylethers are mentioned: methoxy-ethene,ethoxyethene, butoxy and isobutoxyethene and further the compounds ofthe following formulae:

The preparation of the relative alkynyl ethers by means of thesevinylethers takes place according to one of the common methods, forinstance, by means of an acid, such as p-toluene sulphonic acid,dinitrobenzene sulphonic acid or anhydrous hydrochloric acid, or bymeans of a Lewis acid, such as borotrifiuoride-etherate. The reactionmay occur in a medium free from solvent or in an indifferent solvent,such as benzene, petroleumether, chloroform, carbontetrachlolide,dialkylether, for instance, ethoxyethane, and in tetrahydrofuran or in amixture of two or more of these solvents. The formation of the etheroccurs at temperature between 30 C. and 100 C., preferably at roomtemperature.

The alkynylethers formed in this reaction may contain one or twoasymmetric carbon atoms, one of which may be present in the ether groupto be split off. The reaction mixture obtained may therefore be amixture of hardly separable disastereoisomers, which, as a mixture, arefurther converted.

Example 1 (A) To 61.13 gm. of 1,1-dimethoxy-3-hydroxy-3-methyl-hex-S-yne 68.78 gm. of ethyl-vinylether were added and, whilestirring, 0.035 gm. of p toluene sulphonic acid. The temperature rose ina short time to 5 3 C. and fell slowly afterwards. After 1 hoursstirring the reaction mixture was poured out into a saturated sodiumchloride solution to which a small amount of potassium carbonate wasadded. The organic layer formed was separated from the water layer. Thelatter was extracted a few times with ether. The joint organic layerswere next washed to neutral with a saturated sodium chloride solution.After drying on sodium sulphate, followed by filtration, the solventswere evaporated in vacuo. The residue was distilled in vacuo to obtain60.75 gm. of crude 1,1dimethoxy-3-(1-ethoxyethyl)-oxy-3-methylhex-S-yne. Boiling point 77-85C. at 0.5 mm. Hg.

(B) With 48.08 gm. of potassium in 925 ml. of liquid ammonia and 0.62gm. of Fe(NO .9H O a solution was made in the conventional manner of KNHin liquid ammonia. At -40 C. 50 gm. of the ether obtained according to Awere added to it in 45 minutes. After 1 hours stirring 85 gm. ofammonium chloride were added, after which the ammonia was evaporated.Next 475 ml. of water were added, whereupon the mixture was extractedwith hexane. The organic layers were filtered, washed with a saturatedsodium chloride solution and dried on sodium sulphate. After filtration0.25 gm. of a-tocopherol was added. The solvent was afterwardsevaporated in vacuo, whereupon the residue was distilled in vacuo. Thusthe l-methoxy-B-methyl-hexa-1,3-dien-5-yne was obtained with a yield of70% and a boiling point of 27- 29 C. at 0.25 mm. Hg;

)c" 21,500 at. 274 mu max.-

In the way of Example 1, starting from 1,1-diethoxy-3-hydroxy-3-methyl-hex-5-yne and dihydropyran, by means ofa littlep-toluene sulphonic acid as catalyst, the 3-tetrahydropyranylether wasprepared. After isolation and distillation, it was converted at -50 C.into 1-ethoxy-3- methyl-hexa-1,3-dien-5-yne with sodium amide in liquidammonia, in which process 10 mol of sodium amide per mol of ether wereused. After addition of ammonium chloride and water to this reactionmixture, the organic layer formed was extracted with hexane and theextract filtered, washed and dried on Na SO' Finally the hexadienync,after removal of the hexane and distillation, was obtained in a yield of60% relating to the starting product.

Example 3 (A) In 800 ml. of liquid ammonia the sodium amide was madefrom 0.1 mol of sodium and a trace of ferric nitrate. After cooling toC. to 0.1 mol of 3-hydroxy-3-methyl-hex-5-yne, boiling point 48 C. at 13mm. Hg, dissolved in 60 ml. of tetrahydrofuran was added to it. Nextwere added 6.5 ml. of methyliodide. After 3 hours stirring at 75 C. theammonia was evaporated and water was added gently. The water layer wasnext extracted with ether. The organic layers obtained were washed tillneutral reaction. After drying on sodium sulphate the extract wasfiltered and the solvent evaporated in vacuo. Finally the residue wasdistilled in vacuo to obtain crude 3-methoxy-3-methyl-hex-5-yne.

(B) In the conventional manner, from 123 gm. of sodium in 3 l. of liquidammonia, the sodium amide was prepared by means of a little ferricnitrate. To the grey suspension obtained were added at -40 C. 50 gm. of3-methoxy-3-methyl-hex-5-yne in 30' minutes at -40 C. After 4 hoursstirring 300 gm. of solid ammonium chloride were added gently. Next theammonia was evaporated while water was added gently. After extractionwith hexane the organic layers were filtered, washed with a saturatedsodium chloride solution and dried on sodium sulphate. Next the extractwas filtered and 0.25 gm. of a-tocopherol was added. The solvent wasevaporated in vacuo, whereupon the residue was distilled in vacuo. Thusthe 3-methyl-hex-3-en-5-yne was obtained in a yield of 54%.

Example 4 In an analogous manner as described in Example 3 from5-hydroxy-5-methyl-oct-7-yn the S-pyranylether was prepared and afterisolation with KNH in liquid ammonia converted into the5-methyl-octa-5-en-7-yne in a yield of 56 What is claimed is:

1. Process for the manufacture of unsaturated compounds of the formula:

in which, R represents an alkyl group having 1-6- carbon atoms, whichmay be branched and substituted, comprising etherifying the hydroxylgroup of a compound of the formula:

in which R represents an alkyl group with 1-6 carbon atoms, is used asstarting material from which, after 6 etherifying the hyd-roxyl group,two ether groups are split off while forming the compound of theformula:

(EH: HCEC-CH=CCH=CHOR1 3. The process of claim 1 in which the startingproduct is etherified by addition to a vinylether of the formula:

R3-CC-Ru in which R R and R represent a member of the group consistingof hydrogen and an alkyl group with 1-6 carbon atoms and R an alkylgroup with 1-6 carbon atoms.

4. The process of claim 1 in which per mol of ether 5 to 15 mol ofalkali metal amide are used.

References Cited UNITED STATES PATENTS 2,671,112 3/ 1954 Inhoffen260-678 2,676,992 4/1954 Humphlett 260598 2,676,994 4/1954 Burnes et al260--611 DELBERT E. GANTZ, Primary Examiner.

I. D. MYERS, Assistant Examiner.

